Submission Details

The BBS7 gene was first reported in relation to Bardet-Biedl syndrome in a 2003 report of an affected individual from a consanguineous family (PMID: 12567324). Subsequent publications have established that cases diagnosed with Bardet-Biedl syndrome 7 exhibit retinal disease as the most penetrant feature, characterized by retinal dystrophy, often in a cone-rod pattern, photoreceptor layer loss, pigmentary retinopathy, reduced visual acuity, and/or retinal arteriolar constriction. These phenotypes are generally accompanied by diverse extraocular features such as obesity, polydactyly, renal abnormalities including cysts, abnormal morphology of the heart and/or liver, dental abnormalities such as crowding, hypoplastic external genitalia in males, and/or intellectual disability. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic BBS7 loss of function) were found to be consistent among patients diagnosed with Bardet-Biedl syndrome 7 (MIM# 615984), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic BBS7 variants have been lumped into a single disease entity, referred to as BBS7-related ciliopathy.

Nine suspected disease-causing variants have been scored as part of this curation (two nonsense, five frameshift, one affecting splicing, and one missense), which have been collectively reported in seven probands in seven publications (PMID: 12567324, PMID: 19402160, PMID: 24849935, PMID: 25553308, PMID: 26557828, PMID: 26518167, PMID: 30839500). All of the probands scored in this curation harbored biallelic BBS7 variants. The mechanism of pathogenicity appears to be biallelic loss of BBS7 function conferred by null and/or hypomorphic variants. Only two relatively small families were found in the literature (PMID: 12567324, PMID: 30839500), and segregation evidence did not contribute to the scoring of this curation.

This gene-disease association is also supported by biochemical evidence that BBS7 encodes a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 17574030). Consistent with these functions, BBS7 protein localizes to transition zones and ciliary axonemes and dynamically moves in both anterograde and retrograde directions along the ciliary axoneme (PMID: 15231740). BBS7 co-immunoprecipitates with BBS4 (PMID: 17574030), and the genes encoding other BBSome components have similarly been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including BBS1 (PMID: 12118255), BBS2 (PMID: 11285252), ARL6 (PMID: 15258860), BBS4 (PMID: 11381270), BBS5 (PMID: 15137946), MKKS (PMID: 10973238, PMID: 10973251), and TTC8 (PMID: 14520415). C. elegans with biallelic Bbs-7 disruption exhibit short cilia and defects in cilia-based chemotaxis and intraflagellar transport (PMID: 15231740), while bbs7 knockdown in zebrafish disrupts the ciliated organ controlling left-right patterning and triggers a defect in intracellular retrograde transport of melanosomes (PMID: 16399798). Biallelic disruption of BBS7 orthologs in mice or macaques recapitulates many of the features of human patients, including retinal degeneration, abnormal renal morphology, and male reproductive defects (PMID: 23572516, PMID: 31589838).

In summary, BBS7 is definitively associated with BBS7-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on September 7th, 2023 (SOP Version 9).